Abstract:

Disclosed are quinoline compounds having affinity for the 5-HT6
receptor and having the formula:
##STR00001##
where R1, R2, R3, R4, R5, n, m, p and A are
defined herein, and salts thereof, compositions containing these
compounds and salts and processes for making and using the same.

Claims:

1. A method of treating a patient suffering from a disorder selected from
anxiety, depression, epilepsy, an obsessive compulsive disorder,
migraine, Parkinsons Disease, ADHD, a sleep disorder, a feeding disorder,
a panic attack, withdrawal from drug abuse, schizophrenia, stroke, a
disorder associated with spinal trauma and/or head injury and irritable
bowel syndrome, which method comprises administering a therapeutically
effective amount of a compound of formula (I): ##STR00024##
wherein:R1 represents hydrogen, methyl, ethyl, isopropyl, isobutyl
or 2,2-dimethylpropyl;R2 represents hydrogen or methyl or is linked
to R1 to form a group (CH2)3;R3 represents hydrogen,
methyl or halogen;R4 and R5 independently represent hydrogen,
or methyl;m represents 1 or 2, or m is 2 and both R2 groups are
linked to form a CH2 group linking C-2 and C-5 of the piperizine
ring;n represents 1;p represents 1 or 2;A represents a group --Ar1
wherein Ar1 represents unsubstituted phenyl or phenyl substituted by
halogen, cyano, C1-6alkyl, C1-6alkoxy, trifluoromethyl or
trifluoromethoxy,or a pharmaceutically acceptable salt thereof,to a
patient in need thereof.

2. The method according to claim 1, wherein the sleep disorder includes
disturbances of Circadian rhythm.

3. The method according to claim 1, wherein withdrawal from drug abuse is
withdrawal from drug abuse of cocaine, ethanol, nicotine or a
benzodiazepine.

4. The method according to claim 1, wherein the feeding disorder is
selected from anorexia and bulimia.

5. The method according to claim 1, wherein the disorder associated with
spinal trauma and/or head injury is hydrocephalus.

6. The method according to claim 1, wherein the disorder is depression.

7. The method according to claim 1, wherein the disorder is anxiety

8. The method according to claim 1, wherein the disorder is Parkinsons
disease.

9. A method of treating a patient suffering from a cognitive memory
disorder associated with Parkinsons disease, which method comprises
administering a therapeutically effective amount of a compound of formula
(I): ##STR00025## wherein:R1 represents hydrogen, methyl, ethyl,
isopropyl, isobutyl or 2,2-dimethylpropyl;R2 represents hydrogen or
methyl or is linked to R1 to form a group (CH2)3;R3
represents hydrogen, methyl or halogen;R4 and R5 independently
represent hydrogen, or methyl;m represents 1 or 2, or m is 2 and both
R2 groups are linked to form a CH2 group linking C-2 and C-5 of
the piperizine ring;n represents 1;p represents 1 or 2;A represents a
group --Ar1 wherein Ar1 represents unsubstituted phenyl or
phenyl substituted by halogen, cyano, C1-6alkyl, C1-6alkoxy,
trifluoromethyl or trifluoromethoxy,or a pharmaceutically acceptable salt
thereof,to a patient in need thereof.

[0002]This invention relates to novel quinoline compounds having
pharmacological activity, to processes for their preparation, to
compositions containing them and to their use in the treatment of CNS and
other disorders.

[0003]WO 98/27081 discloses a series of aryl sulphonamide compounds that
are said to be 5-HT6 receptor antagonists and which are claimed to
be useful in the treatment of various CNS disorders. GB-2341549, WO
99/47516 and WO 99/65906 all disclose a series of indole derivatives that
are claimed to have 5-HT6 receptor affinity. JP 02262627 (Japan
Synthetic Rubber Co) describes a series of substituted quinoline
derivatives useful as wavelength converting elements. WO 00/42026 (Novo
Nordisk) describes a series of quinoline and quinoxaline compounds for
use as GLP-1 agonists.

SUMMARY OF THE INVENTION

[0004]A structurally novel class of compounds has now been found which
also possess affinity for the 5-HT6 receptor. The present invention
therefore provides, in a first aspect, a compound of formula (I) or a
pharmaceutically acceptable salt thereof:

##STR00002##

[0005]wherein:

[0006]R1 and R2 independently represent hydrogen or C1-6
alkyl or R1 is linked to R2 to form a group (CH2)2,
(CH2)3or (CH2)4;

[0021]Alkyl groups, whether alone or as part of another group, may be
straight chain or branched and the groups alkoxy and alkanoyl shall be
interpreted similarly. Alkyl moieties are more preferably C1-4
alkyl, eg. methyl or ethyl. The term `halogen` is used herein to
describe, unless otherwise stated, a group selected from fluorine,
chlorine, bromine or iodine.

[0024]It will be appreciated that wherein the above mentioned aryl or
heteroaryl groups have more than one substituent, said substituents may
be linked to form a ring, for example a carboxyl and amine group may be
linked to form an amide group.

[0034]When A represents a group --Ar2--Ar3, Ar2 and
Ar3 preferably both independently represent phenyl or monocyclic
heteroaryl group as defined above.

[0035]Preferably A represents a group --Ar1.

[0036]Most preferred --Ar1 is unsubstituted phenyl.

[0037]Preferred compounds according to the invention include examples
E1-E43 as shown below, or a pharmaceutically acceptable salt thereof.

[0038]The compounds of formula (I) can form acid addition salts thereof.
It will be appreciated that for use in medicine the salts of the
compounds of formula (I) should be pharmaceutically acceptable. Suitable
pharmaceutically acceptable salts will be apparent to those skilled in
the art and include those described in J. Pharm. Sci., 1977, 66, 1-19,
such as acid addition salts formed with inorganic acids e.g.
hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and
organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,
benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
The present invention includes within its scope all possible
stoichiometric and non-stoichiometric forms.

[0039]The compounds of formula (I) may be prepared in crystalline or
non-crystalline form, and, if crystalline, may optionally be solvated,
eg. as the hydrate. This invention includes within its scope
stoichiometric solvates (eg. hydrates) as well as compounds containing
variable amounts of solvent (eg. water).

[0040]Certain compounds of formula (I) are capable of existing in
stereoisomeric forms (e.g. diastereomers and enantiomers) and the
invention extends to each of these stereoisomeric forms and to mixtures
thereof including racemates. The different stereoisomeric forms may be
separated one from the other by the usual methods, or any given isomer
may be obtained by stereospecific or asymmetric synthesis. The invention
also extends to any tautomeric forms and mixtures thereof.

[0041]A more preferred compound according to the invention includes
3-phenylsulfonyl-8-piperazin-1-yl-quinoline or a pharmaceutically
acceptable salt thereof (eg. as the hydrochloride salt), most preferably
as the free base (eg. 3-phenylsulfonyl-8-piperazin-1-yl-quinoline).

[0042]It has been found that the free base of
3-phenylsulfonyl-8-piperazin-1-yl-quinoline exists in more than one
polymorphic form. The present invention extends to all such forms whether
in a pure polymorphic form or when admixed with any other material, such
as another polymorphic form. Herein, the polymorphic forms of the free
base are referred to as Form I and Form II. Each of the said forms may
also be referred to herein as the free base as appropriate.

[0043]Suitably, the invention provides the free base, suitably as
characterised by data provided by at least one of the following:
infrared, Raman, X-ray powder diffraction or nuclear magnetic resonance
and melting point data as provided herein, including partial spectral
data provided herein.

[0044]In a further aspect the invention provides
3-phenylsulfonyl-8-piperazin-1-yl-quinoline Form I.

[0045]In a further aspect the invention provides
3-phenylsulfonyl-8-piperazin-1-yl-quinoline Form II.

[0054]As a consequence of greater stability provided by a higher melting
point, 3-phenylsulfonyl-8-piperazin-1-yl-quinoline (Form II) is the
preferred form of 3-phenylsulfonyl-8-piperazin-1-yl-quinoline.

[0055]The present invention also provides a process for the preparation of
a compound of formula (I) or a pharmaceutically acceptable salt thereof,
which process comprises:

[0056](a) reacting a compound of formula (II)

##STR00003##

[0057]wherein R1a is as defined for R1 or an N-protecting group,
R2, R3, R4, R5, m, n and p are as defined above and
L1 is a leaving group such as iodo or trifluoromethylsulfonyloxy;
with a compound of formula A-SO2H, (or A-SH followed by a subsequent
oxidation step) wherein A is as defined above and thereafter as necessary
removing an R1a N-protecting group;

[0058](b) deprotecting a compound of formula (I) which is protected; and
thereafter optionally

[0060]The present invention also provides a further process for the
preparation of a compound of formula (I) or a pharmaceutically acceptable
salt thereof, which process comprises:

[0061](d) reacting a compound of formula (IV)

##STR00004##

[0062]with a compound of formula (V)

##STR00005##

[0063]wherein R1a, R2, R3, R4, R5, A, m, n and p
are as defined above, and L2 represents a suitable leaving group,
such as a halogen atom and thereafter as necessary removing an R1a
N-protecting group; or

[0064](e) reacting a compound of formula (VI)

##STR00006##

[0065]with a compound of formula (VII)

##STR00007##

[0066]wherein R1a, R2, R3, R4, R5, m, n, p and A
are as defined above and L3 represents a suitable leaving group,
such as a halogen atom (e.g. a bromine or iodine atom) or a
trifluoromethylsulfonyloxy group, and thereafter as necessary removing an
R1a N-protecting group. The N-protecting group used may be any
conventional group e.g. t-butyloxy carbonyl (Boc) or benzyloxycarbonyl.
Further N-protecting groups which may be used include methyl.

[0067]Process (a) wherein a compound of formula (II) is reacted with a
compound of formula A-SO2H typically comprises use of basic
conditions and may be most conveniently carried out by using a suitable
salt of the compound A-SO2H (e.g. the sodium salt) in an appropriate
solvent such as N,N-dimethylformamide, in the presence of a transition
metal salt such as copper (I) iodide.

[0068]Process (a) wherein a compound of formula (II) is reacted with a
compound of formula A-SH typically comprises use of basic conditions e.g.
by using a suitable salt of the compound A-SH (e.g. the sodium salt) in
an appropriate solvent such as N,N-dimethylformamide, in the presence of
a suitable metal salt such as copper (I) iodide, followed by use of a
suitable oxidant such as 3-chloroperbenzoic acid, peracetic acid or
potassium monopersulfate.

[0069]In processes (a) and (b), examples of protecting groups and the
means for their removal can be found in T. W. Greene `Protective Groups
in Organic Synthesis` (J. Wiley and Sons, 1991). Suitable amine
protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl,
2',2',2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl)
and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.
using an acid such as hydrochloric acid) or reductively (e.g.
hydrogenolysis of a benzyl group or reductive removal of a
2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid) as
appropriate. Other suitable amine protecting groups include
trifluoroacetyl (--COCF3) which may be removed by base catalysed
hydrolysis or a solid phase resin bound benzyl group, such as a
Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which
may be removed by acid catalysed hydrolysis, for example with
trifluoroacetic acid. A further amine protecting group includes methyl
which may be removed using standard methods for N-dealkylation (e.g.
1-chloroethyl chloroformate under basic conditions followed by treatment
with methanol).

[0070]Process (c) may be performed using conventional interconversion
procedures such as epimerisation, oxidation, reduction, reductive
alkylation, alkylation, nucleophilic or electrophilic aromatic
substitution, ester hydrolysis or amide bond formation. For example,
N-dealkylation of a compound of formula (I) wherein R1 represents an
alkyl group to give a compound of formula (I) wherein R1 represents
hydrogen. It will be appreciated that such interconversion may be
interconversion of protected derivatives of formula (I) which may
subsequently be deprotected following interconversion.

[0071]In addition, process (c) may comprise, for example, reacting a
compound of formula (I), wherein R1 represents hydrogen, with an
aldehyde or ketone in the presence of a reducing agent in order to
generate a compound of formula (I) where R1 represents
C1-6alkyl. This may be performed using a hydride donor agent such as
sodium cyanoborohydride, sodium triacetoxyborohydride or a resin bound
form of cyanoborohydride in an alcoholic solvent such as ethanol and in
the presence of an acid such as acetic acid, or under conditions of
catalytic hydrogenation. Alternatively, such a transformation may be
carried out by reacting a compound of formula (I), wherein R1
represents hydrogen, with a compound of formula R1-L, wherein
R1 is as defined above and L represents a leaving group such as a
halogen atom (e.g. bromine or iodine) or methylsulfonyloxy group,
optionally in the presence of a suitable base such as potassium carbonate
or triethylamine using an appropriate solvent such as
N,N-dimethylformamide or a C1-4alkanol.

[0072]Process (d) may be performed in the presence of a suitable base,
such as sodium carbonate and the use of a suitable solvent such as
n-butanol.

[0073]Process (e) may be performed in the presence of a palladium, nickel
or copper catalyst, for example a mixture of a palladium source such as
Pd2(dba)3 and a suitable ligand such as (R)-, (S)- or
(±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) or
(2-dicyclohexylphosphanylphenyl)-dimethylamine or
1,1'-bis-diphenylphosphinoferrocene, together with a suitable base such
as sodium t-butoxide, in an inert solvent such as 1,4-dioxane.

[0074]Compounds of formula (II) may be prepared by reacting a compound of
formula (III)

##STR00008##

[0075]wherein R3, R4, R5, n and L1 are as defined
above, with a compound of formula (IV) as defined above. This process
typically comprises the use of a suitable base, such as sodium carbonate
and the use of a suitable solvent such as n-butanol.

[0076]Compounds of formula (V) may be prepared in accordance with the
following scheme:

##STR00009##

[0077]wherein R3, R4, R5, n, A and L1 are as defined
above.

[0078]Step (i) typically comprises reaction of a compound of formula
(VIII) with a compound of formula A-SO2-M, wherein A is as defined
above and M is a metal residue such as sodium or potassium, in the
presence of a copper(I)salt, e.g. copper(I)triflate or copper(I)iodide,
in a suitable solvent such as anhydrous N,N-dimethylformamide or
1,4-dioxane, optionally including a ligand such as
N,N-dimethyl-ethylene-1,2-diamine.

[0079]Alternatively, the transformation shown in step (i) may be carried
out using a two step procedure typically comprising steps (iii) and (iv).

[0080]Step (iii) typically comprises the reaction of a compound of formula
(VIII) with a compound of formula A-SH, wherein A is as defined above, in
the presence of a base such as sodium hydride or potassium phosphate in a
suitable solvent such as anhydrous N,N-dimethylformamide or ethylene
glycol, optionally in the presence of a copper(I)iodide catalyst.

[0083]Compounds of formula (VI) wherein L3 represents a halogen atom
may be prepared in accordance with the following scheme:

##STR00010##

[0084]wherein R3, R4, R5, n and A are as defined above and
Hal represents a halogen atom.

[0085]Step (i) typically comprises diazotisation according to known
methods (e.g. using sodium nitrite with aqueous inorganic acid as
solvent, or an alkyl nitrite ester using a suitable solvent such as
acetonitrile in the presence of anhydrous acid e.g. trifluoroacetic
acid), followed by treatment of the resulting diazonium salt with an
appropriate halide salt such as copper (I) bromide, potassium iodide or
tetrabutylammonium iodide. Such a procedure may be carried out in aqueous
solution or using anhydrous conditions, for example using trifluoroacetic
acid as solvent.

[0086]Compounds of formula (VI) wherein L3 represents a halogen atom
may also be prepared in accordance with the following scheme:

##STR00011##

[0087]wherein R3, R4, R5, A and n are as defined above and
Hal represents a halogen atom.

[0088]Step (i) typically comprises the use of a suitable reducing agent
such as iron powder, to give a compound of formula (XI).

[0089]Step (ii) typically comprises a diazotisation reaction using an
aqueous or non-aqueous source of nitrosonium ions as described above,
followed by conversion to a halide.

[0090]Step (iii) typically comprises the use of a suitable oxidant such as
monomagnesium peroxyphthalate.

[0091]Compounds of formula (VI) wherein L3 represents a
trifluoromethylsulfonyloxy group may be prepared from compounds of
formula (V) as defined above, by diazotisation according to known
methods, followed by heating under acidic conditions, followed by
treatment with trifluoromethylsulfonic anhydride in the presence of a
base, such as pyridine.

[0092]Compounds of formula (III), (IV), (VII) and (VIII) are known in the
literature or can be prepared by analogous methods.

[0093]Pharmaceutically acceptable salts may be prepared conventionally by
reaction with the appropriate acid or acid derivative.

[0094]Compounds of formula (I) and their pharmaceutically acceptable salts
have affinity for the 5-HT6 receptor and are believed to be of
potential use in the treatment of certain CNS disorders such as anxiety,
depression, epilepsy, obsessive compulsive disorders, migraine, cognitive
memory disorders (e.g. Alzheimers disease, age related cognitive decline
and mild cognitive impairment), Parkinsons Disease, ADHD (Attention
Deficit Disorder/Hyperactivity Syndrome), sleep disorders (including
disturbances of Circadian rhythm), feeding disorders such as anorexia and
bulimia, panic attacks, withdrawal from drug abuse such as cocaine,
ethanol, nicotine and benzodiazepines, schizophrenia (in particular
cognitive deficits of schizophrenia), stroke and also disorders
associated with spinal trauma and/or head injury such as hydrocephalus.
Compounds of the invention are also expected to be of use in the
treatment of certain GI (gastrointestinal) disorders such as IBS
(Irritable Bowel Syndrome). Compounds of the invention are also expected
to be of use in the treatment of obesity.

[0095]Thus the invention also provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof, for use as a therapeutic
substance, in particular in the treatment or prophylaxis of the above
disorders. In particular the invention provides for a compound of formula
(I) or a pharmaceutically acceptable salt thereof, for use in the
treatment of depression, anxiety, Alzheimers disease, age related
cognitive decline, ADHD, obesity, mild cognitive impairment,
schizophrenia, cognitive deficits in schizophrenia and stroke.

[0096]The invention further provides a method of treatment or prophylaxis
of the above disorders, in mammals including humans, which comprises
administering to the sufferer a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0097]In another aspect, the invention provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament for use in the treatment or prophylaxis of
the above disorders.

[0098]5-HT6 antagonists have the potential to be capable of
increasing basal and learning-induced polysialylated neuron cell
frequency in brain regions such as the rat medial temporal lobe and
associated hippocampus, as described in International Patent Application
No. PCT/EP03/00462. Thus, according to a further aspect of the present
invention, we provide a method of promoting neuronal growth within the
central nervous system of a mammal which comprises the step of
administering a compound of formula (I) or a pharmaceutically acceptable
salt thereof.

[0099]In order to use the compounds of formula (I) in therapy, they will
normally be formulated into a pharmaceutical composition in accordance
with standard pharmaceutical practice. The present invention also
provides a pharmaceutical composition, which comprises a compound of
formula (I) or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.

[0100]A pharmaceutical composition of the invention, which may be prepared
by admixture, suitably at ambient temperature and atmospheric pressure,
is usually adapted for oral, parenteral or rectal administration and, as
such, may be in the form of tablets, capsules, oral liquid preparations,
powders, granules, lozenges, reconstitutable powders, injectable or
infusable solutions or suspensions or suppositories. Orally administrable
compositions are generally preferred.

[0101]Tablets and capsules for oral administration may be in unit dose
form, and may contain conventional excipients, such as binding agents,
fillers, tabletting lubricants, disintegrants and acceptable wetting
agents. The tablets may be coated according to methods well known in
normal pharmaceutical practice.

[0102]Oral liquid preparations may be in the form of, for example, aqueous
or oily suspension, solutions, emulsions, syrups or elixirs, or may be in
the form of a dry product for reconstitution with water or other suitable
vehicle before use. Such liquid preparations may contain conventional
additives such as suspending agents, emulsifying agents, non-aqueous
vehicles (which may include edible oils), preservatives, and, if desired,
conventional flavourings or colourants.

[0103]For parenteral administration, fluid unit dosage forms are prepared
utilising a compound of the invention or pharmaceutically acceptable salt
thereof and a sterile vehicle. The compound, depending on the vehicle and
concentration used, can be either suspended or dissolved in the vehicle.
In preparing solutions, the compound can be dissolved for injection and
filter sterilised before filling into a suitable vial or ampoule and
sealing. Advantageously, adjuvants such as a local anaesthetic,
preservatives and buffering agents are dissolved in the vehicle. To
enhance the stability, the composition can be frozen after filling into
the vial and the water removed under vacuum. Parenteral suspensions are
prepared in substantially the same manner, except that the compound is
suspended in the vehicle instead of being dissolved, and sterilization
cannot be accomplished by filtration. The compound can be sterilised by
exposure to ethylene oxide before suspension in a sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the
composition to facilitate uniform distribution of the compound.

[0104]The composition may contain from 0.1% to 99% by weight, preferably
from 10 to 60% by weight, of the active material, depending on the method
of administration.

[0105]The dose of the compound used in the treatment of the aforementioned
disorders will vary in the usual way with the seriousness of the
disorders, the weight of the sufferer, and other similar factors.
However, as a general guide suitable unit doses may be 0.05 to 1000 mg,
more suitably 0.05 to 200 mg, for example 20 to 40 mg; and such unit
doses will preferably be administered once a day, although administration
more than once a day may be required; and such therapy may extend for a
number of weeks or months.

[0106]All publications, including but not limited to patents and patent
applications, cited in this specification are herein incorporated by
reference as if each individual publication were specifically and
individually indicated to be incorporated by reference herein as though
fully set forth.

[0107]The following Descriptions and Examples illustrate the preparation
of compounds of the invention.

[0108]Description 1

3-Bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1)

[0109]bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol)
and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of
3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon
et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred
suspension was heated at reflux for 72 h. The reaction mixture was cooled
to ambient temperature, diluted with dichloromethane (300 ml) and the
solution washed with water (300 ml), dried (MgSO4) and concentrated
in vacuo to an oil. The oil was purified by chromatography over silica
gel eluting with a gradient of methanol/dichloromethane to afford the
title compound (D1) as an oil (2.6 g, 8.5 mmol, 49%);

[0113]A mixture of 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1)(1.75
g, 5.7 mmol), copper(I)iodide (5.4 g, 28.5 mmol) and potassium iodide
(9.6 g, 57.8 mmol) in hexamethylphosphoramide (20 ml) was heated in an
oil bath at 150° C. for 21 h under argon. To the cooled reaction
mixture was added toluene (120 ml) and 1M hydrochloric acid (120 ml) and
the whole was shaken vigorously for 5 minutes. The insoluble brown solid
was then collected by filtration, washed with methanol (3×40 ml)
and resuspended in a mixture of dichloromethane (150 ml) and 2M sodium
hydroxide (150 ml). After shaking the mixture vigorously, the insoluble
material was filtered, washed with dichloromethane (2×50 ml) and
discarded. The filtrate and washings were transferred to a separating
funnel and the layers were separated. The aqueous phase was extracted
with dichloromethane (2×100 ml) and the combined organic extracts
were dried (MgSO4) and concentrated to a brown oil (1.5 g) which was
identified by NMR spectroscopy as a mixture of the title compound (D2)
and 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1) in a ratio of 4:1.
This mixture was used directly in the next stage (see Example 1).

[0117]A stirred mixture of 8-nitroquinoline (100 g, 0.57 mol) in acetic
acid (500 ml) was treated with N-iodosuccinimide (155 g, 0.69 mol)
portionwise over 10 minutes, and warmed to 62° C. for 6 h. A
further portion of N-iodosuccinimide (25 g, 0.14 mol) was introduced and
the mixture stirred for a further 16 h before cooling to ambient
temperature. The solvent was removed in vacuo, keeping the temperature
below 35° C. The residue was dissolved in dichloromethane (2 L)
and washed successively with saturated aqueous sodium bicarbonate
solution (2×1 L), 10% aqueous sodium thiosulphate solution (1 L),
water (1 L), brine (100 ml), then the organic phase was dried over
magnesium sulphate. The mixture was filtered and the solvent removed to
give a yellow solid which was recrystallised from ethyl acetate to give
the title compound (D3) (168 g, 97%) as a yellow solid;

[0121]3-Iodo-8-nitroquinoline (D3) (135 g, 0.45 mol), was suspended in
dimethylformamide (2.4 L) in a 5 L 3-necked flask fitted with an overhead
stirrer, under an argon atmosphere. This mixture was treated successively
with anhydrous sodium phenylsulfinate (99.6 g 0.608 mol), and
bis-(copper(I)triflate)benzene complex (170 g, 0.338 mol). The resulting
slurry was heated to 65° C. for 18 h. The mixture was cooled,
filtered and the solvent evaporated in vacuo. Acetone (2.5 L) was added
to the residue and the solution filtered. The filtrate was evaporated in
vacuo, a further 2.5 L of acetone added and the mixture filtered again.
The solvent was evaporated in vacuo and the residue dissolved in
chloroform (3 L) and washed with 10% aqueous ammonia (2×2 L), and
the organic phase was dried over magnesium sulphate and the solvent
evaporated in vacuo. The dark brown residue was purified using a Biotage
flash-150 chromatography apparatus (5 kg silica gel) eluting with hexane
and increasing proportions of ethyl acetate to give the title compound
(D4) (81.5 g, 58%) as a yellow solid;

[0125]A slurry of 8-nitro-3-phenylsulfonylquinoline (D4) (46.7 g, 172
mmol), in tetrahydrofuran (750 ml) was added to a stirred solution of 30%
titanium(III)chloride in aqueous HCl (470 ml) [Supplied by BDH] cooled in
an ice bath, at such a rate that the temperature was maintained below
35° C. Once the addition was completed, the solution was stirred
for a further 10 minutes then water (1.5 L) was introduced and the
mixture poured into a 5 L beaker. The rapidly stirred solution was
treated by portionwise addition of solid potassium carbonate in order to
attain pH ˜8.5. EDTA (250 g, 0.86 mol) was added and followed by
further potassium carbonate to maintain pH ˜8.5. The mixture was
extracted with dichloromethane (3×1 L) and the combined organic
phase passed through a silica plug (500 g) eluting with further
dichloromethane (1 L) and 10% ethyl acetate in dichloromethane (1 L). The
combined organic phases were evaporated and the residue subjected to
purification using Biotage Flash-75 chromatography apparatus (2 kg silica
gel), eluting with dichloromethane and increasing proportions of ether to
give the title compound (D5) (34.5 g, 72%) as a pale brown solid;

[0132]8-Iodo-3-phenylsulfonylquinoline (D6) (25.2 g, 63.6 mmol) was
dissolved in dry, de-gassed dioxan (500 ml) under argon. To this solution
was added sodium t-butoxide (8.56 g, 89.2 mmol) and 1-t-butyloxycarbonyl
piperazine (14.2 g, 76.4 mmol) followed by a suspension of catalyst under
argon. The catalyst was prepared by sonication of a mixture of
tris-(dibenzylideneacetone)dipalladium(0) (1.75 g, 1.91 mmol) and
2-dicyclohexylphosphino-2'-(N,N-dimethyl amino)biphenyl (2.25 g, 5.73
mmol) in dry degassed dioxane (10 ml) for 2 minutes. This mixture was
stirred at 40° C. for 5 h after which a further charge of catalyst
was administered (prepared as above on half the scale) and stirring
continued for 16 h at 40° C.

[0133]The mixture was filtered and the solvent removed. The residue was
adsorbed onto silica and chromatographed on silica eluting with 1%
methanol in dichloromethane to give the title compound (D7) (22.0 g, 76%)
as a yellow solid;

[0206]To a suspension of sodium hydride (0.16 g, 6.67 mmol) in
dimethylformamide (10 ml) was slowly added 2-chlorothiophenol (0.96 g,
6.67 mmol) as a solution in dimethylformamide (5 ml). The reaction
mixture was stirred for 10 minutes, then a solution of
3-iodo-8-nitroquinoline (D3) (1.0 g, 3.33 mmol) in dimethylformamide (5
ml) was added slowly and the mixture heated to 90° C. for 4 hours.
The mixture was cooled to ambient temperature, then water (50 ml) was
added carefully and the mixture extracted with dichloromethane
(2×50 ml). The organic phase was washed with brine (50 ml), dried
over magnesium sulfate and concentrated in vacuo. The crude material was
purified by chromatography on silica, eluting with a hexane/ethyl acetate
gradient to provide the title compound (D26) (0.70 g, 70%) as a brown
oil;

[0248]A solution of sodium nitrite (5.44 g, 78.8 mmol, 1.2 eq) in water
(125 ml, 5 vol) was added to a stirred slurry of
8-amino-3-phenylsulfonylquinoline methanesulfonic acid salt (D35) (25.0
g, 65.7 mmol) in 5M HCl (500 ml, 20 vol). The mixture was stirred at
23° to 24.5° C. for 1 hr 5 min then acetonitrile (200 ml,
8vol) was added. After 10 min a solution of sodium iodide (14.8 g, 98.6
mmol, 1.5 eq) in water (125 ml, 5 vol) was added over 3 min, resulting in
the formation of a brown mixture and the evolution of gas. The brown
mixture was stirred at 25° C. to 23° C. for 1 hr 5 min then
dichloromethane (500 ml, 20 vol) was added and the mixture was stirred
for 5 min. The lower organic layer was removed and the aqueous layer was
extracted with dichloromethane (125 ml, 5 vol). The combined organic
layers were washed with 10% w/v sodium sulfite (125 ml, 5 vol) then
concentrated under reduced pressure. The resulting mixture was filtered
and the cake was washed with acetonitrile (2×25 ml) and dried in a
40° C. oven under reduced pressure to afford the title compound
D6; yield 15.27 g, 59%, identical spectroscopically to that produced by
the first method.

[0249]General Procedure 2

[0250]The following intermediates were used to prepare Examples 21, 25-28,
32 and 33.

[0251]Description 36

8-Nitro-3-(3-fluorophenyl)-sulfanylquinoline (D36)

[0252]A suspension of 3-iodo-8-nitroquinoline (D3) (4.5 g, 15 mmol),
copper(I)iodide (150 mg, 0.8 mmol, 5 mol %), potassium phosphate (7.0 g,
2 eq), ethylene glycol (45 ml) and 3-fluorobenzenethiol (2.88 g, 22.5
mmol) was stirred and heated at 80° C. for 3.5 hours. The reaction
mixture was cooled to 20° C. then H2O (45 ml) and
dichloromethane (70 ml) were added, the mixture was stirred for 5 minutes
then the lower organic layer was removed (contained solids). Charcoal (2
g, Norit SX) was added to the organic layer and the mixture was stirred
at room temperature for 15 min then filtered The filter cake was rinsed
with dichloromethane (40 ml) and the combined filtrate was washed with
H2O (100 ml). The dichloromethane layer was evaporated to give the
title compound as a yellow solid;

[0256]A suspension of iron powder (1.7 g, 30.4 mmol) in THF (20 ml), water
(2 ml) and acetic acid (1.2 ml, 21 mmol) was heated to 50° C.
8-nitro-3-(3-fluorophenyl)-sulfanylquinoline (D36) (1.8 g, 6 mmol) was
then added portionwise to the mixture over 15 minutes, keeping the
temperature below 60° C. The reaction mixture was then stirred at
60° C. for 5 hours before the addition of toluene (5 ml). After
allowing to cool to 60° C., the mixture was filtered through a
silica plug, washing with toluene (2×20 ml). The volatiles were
removed in vacuo and the residue purified by chromatography over silica
gel, eluting with a gradient of ethyl acetate/hexane to afford the title
compound as a solid (1.6 g, 5.7 mmol, 96%);

[0260]A solution of 8-amino-3-(3-fluoro)-phenylsulfanylquinoline (D37)
(1.4 g, 5.2 mmol) in trifluoroacetic acid (5 ml) was concentrated in
vacuo and the resulting oil dissolved in acetonitrile (10 ml). This was
then added dropwise to an ice-cooled solution of n-butylnitrite (0.91 ml,
7.78 mmol) in acetonitrile (10 ml). The reaction mixture was then stirred
at this temperature for 10 minutes followed by the portionwise addition
of tetra-n-butylammonium iodide (3.8 g, 10.4 mmol). After allowing to
stir at ambient temperature for 1 hour, the mixture was concentrated in
vacuo and the residue purified by chromatography over silica gel, eluting
with a gradient of ethyl acetate/hexane to afford the title compound
(D38) as a solid (1.13 g, 3.0 mmol, 57%);

[0261]Mass Spectrum: C15H9NSFl requires 281; found 282
(MH.sup.+).

[0262]Description 39

8-Iodo-3-(3-fluoro)-phenylsulfonylquinoline (D39)

[0263]A solution of 8-Iodo-3-(3-fluoro)-phenylsulfanylquinoline (D38) (754
mg 2.0 mmol) in dichloromethane (10 ml) was treated with a solution of
monomagnesium peroxyphthalate hexahydrate (2 g, technical) in methanol (3
ml). The mixture was warmed to 40° C. for 12 hours, then treated
with 10% aqueous sodium sulfite (20 ml) and dichloromethane (20 ml). The
organic phase was separated and washed successively with sat. aq. sodium
bicarbonate solution (20 ml) and brine (5 ml), before being concentrated
and the residue purified by flash chromatography on silica gel (eluting
with hexane-dichloromethane) to afford the title compound (D39) as a pale
yellow solid in 50% yield;

[0266]A 4:1 mixture of 3-iodo-8-(4-methyl-piperazin-1-yl)-quinoline (D2)
and 3-bromo-8-(4-methyl-piperazin-1-yl)-quinoline (D1) (1.5 g),
phenylsulfinic acid sodium salt, dihydrate (2.52 g, 12.6 mmol) and
copper(I)iodide (2.4 g, 12.6 mmol) in N,N-dimethylformamide (25 ml) was
stirred in an oil bath at 120° C. for 40 h under argon. To the
reaction mixture, cooled to ambient temperature, was added 5% sodium
hydrogen carbonate solution (100 ml) and dichloromethane (100 ml) with
vigorous shaking. The insoluble material was filtered, washed with
dichloromethane (3×20 ml) and discarded. The filtrate and washings
were transferred to a separating funnel and the layers separated. The
aqueous layer was extracted with dichloromethane (100 ml) and the
combined organic extracts were washed with water (100 ml), dried
(MgSO4) and concentrated in vacuo to an oil (0.9 g). The oil was
purified by chromatography over silica gel eluting with a gradient of
methanol/dichloromethane to afford an orange oil (0.28 g, Rf 0.11,
methanol/dichloromethane 1:19). This material was further purified by
passage through a strong cation exchange (SCX) column eluting firstly
with methanol (fractions discarded) and then with methanol/aqueous
ammonia-880 (10:1) to give the title compound (E1) as an orange oil
(0.152 g, 0.41 mmol, 7% over two steps);

[0269]A solution of 8-amino-3-phenylsulfonylquinoline (D5) (38.8 g, 137
mmol) in n-butanol (360 ml) was treated with
bis-(2-chloroethyl)-methyl-amine hydrochloride (40 g, 138 mmol) and
sodium carbonate (72 g, 0.68 mol). The mixture was heated to a vigorous
reflux (˜100° C.) for 16 h then a further portion of
bis-(2-chloroethyl)-methyl-amine hydrochloride (25 g, 86 mmol) introduced
and heating continued for a further 4 h. The solution was cooled and a
1:1 mixture of saturated aqueous sodium bicarbonate and aqueous 10%
sodium thiosulphate solution (2 L) added. Stirring was continued at
ambient temperature for 16 h then the aqueous phase was extracted with
dichloromethane (3×500 ml), the combined organic phase dried over
magnesium sulphate, evaporated in vacuo and subjected to chromatography
on a Biotage Flash 75 apparatus (1 kg Silica gel) to afford the title
compound (E1) as the free base form (11.6 g), identical spectroscopically
to that prepared by the first method.

[0270]A portion of this material was treated with 1M HCl in ether then
evaporated to afford the hydrochloride salt as a yellow solid;

[0274]A stirred solution of
8-(4-methyl-piperazin-1-yl)-3-phenylsulfonylquinoline (E1) (0.148 g, 0.4
mmol), 1-chloroethyl chloroformate (0.093 ml, 0.85 mmol) and
N,N-diisopropylethylamine (0.148 ml, 0.85 mmol) in 1,2-dichloroethane (9
ml) was heated at reflux for 1.25 h under argon. The reaction mixture was
cooled to ambient temperature and concentrated in vacuo to an oil. The
oil was purified by chromatography over silica gel eluting with a
gradient of methanol/dichloromethane, pooling fractions which contained
the major component (Rf 0.9, methanol/dichloromethane 1:19). The purified
material was redissolved in methanol (15 ml) and the solution was
refluxed for 1 h under argon. The reaction mixture was cooled to ambient
temperature and concentrated in vacuo to a solid which was stirred with
diethyl ether (5 ml) and filtered to afford the title compound (E2) (0.08
g, 0.21 mmol, 51%);

[0277]A mixture of
8-(4-t-butoxycarbonyl)piperazin-1-yl-3-phenylsulfonylquinoline (D7),
1,4-dioxane and 4 M aqueous HCl, was stirred at ambient temperature for
two hours, then the solvent evaporated. The residue was co-evaporated
several times from toluene and the remainder crystallised from hot
ethanol to give the title compound (E2) as a yellow crystalline solid;

[0281]bis-(2-Chloro-ethyl)-amine hydrochloride (0.36 g, 1.89 mmol) and
sodium carbonate (0.50 g, 4.72 mmol) were added to a suspension of
8-amino-3-(2-chloro)phenylsulfonylquinoline (D10) (0.30 g, 0.94 mmol), in
n-butanol (10 ml). The stirred suspension was heated at reflux for 48 h.
The reaction mixture was cooled to ambient temperature, diluted with
dichloromethane (50 ml) and the solution washed with water (50 ml), dried
(MgSO4) and concentrated in vacuo to an oil. The oil was purified by
chromatography over silica gel eluting with a gradient of
methanol/dichloromethane to afford
3-(2-chlorophenylsulfonyl)-8-(4-methylpiperazin-1-yl)quinoline as an oil
(0.17 g, 44%). A stirred solution of
3-(2-chlorophenylsulfonyl)-8-(4-methylpiperazin-1-yl)quinoline (0.17 g,
0.42 mmol), 1-chloroethyl chloroformate (0.14 ml, 1,27 mmol) and
N,N-diisopropylethylamine (0.22 ml, 1.27 mmol) in 1,2-dichloroethane (8
ml) was heated at reflux for 1 h under argon. The reaction mixture was
cooled to ambient temperature and concentrated in vacuo to an oil. This
material was redissolved in methanol (10 ml) and the solution was
refluxed for 1 h under argon. The reaction mixture was cooled to ambient
temperature and concentrated in vacuo to a solid which was purified by
preparative HPLC. The pure material was stirred with 1 M HCl/diethyl
ether (5 ml) and methanol (5 ml), then the resulting mixture was
evaporated in vacuo to afford the title compound (E3);

[0308]8-Iodo-3-phenylsulfonylquinoline (D6) (200 mg, 0.51 mmol) was
dissolved in dry, de-gassed dioxane (4 ml) under argon. To this solution
was added sodium t-butoxide (68 mg, 0.71 mmol) and
(R)-(-)-2-methylpiperazine (61 mg, 0.61 mmol) followed by a suspension of
catalyst under argon. The catalyst was prepared by sonicating
tris-(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol) and
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (18 mg, 0.015
mmol) in dry degassed dioxane (1 ml) for 2 minutes. This mixture was
stirred at 40° C. for 5 h then a further charge of catalyst was
administered (prepared as above on half the scale) and stirring continued
for 16 h at 40° C.

[0309]The mixture was filtered and the solvent removed. The residue was
dissolved in methanol and passed down an SCX ion exchange column eluting
with methanol to remove impurities. The product was recovered by eluting
with 15% 0.880 aqueous ammonia in methanol. The solvent was removed and
the residue dissolved in methanol and treated with a solution of hydrogen
chloride in diethyl ether (1 M). The solvent was removed and the residue
recrystallised from ethanol to afford the title compound (E12) (40 mg
16%);

[0312]Prepared from (S)-(+)-2-methylpiperazine in place of
(R)-(-)-2-methylpiperazine using an analogous process to that described
in Example 12 (E12) affording the title compound (E13) (77 mg, 37%) as a
yellow solid;

[0316]Crude
8-(4-t-butoxycarbonyl)homopiperazin-1-yl-3-phenylsulfonylquinoline (D9)
was suspended in a mixture of dioxane (2 ml) and 4 M hydrochloric acid (2
ml) and stirred at 80° C. for 1 h to form a homogeneous solution.
The solvents were removed and the residue dissolved in methanol and
passed down an SCX ion exchange column eluting with methanol. The product
was recovered by further elution with 15% 0.880 aqueous ammonia in
methanol. The solvents were removed and residue treated with a solution
of hydrogen chloride in diethyl ether (1M). The solvents were removed and
the residue recrystallised from ethanol to afford the title compound
(E14) (20 mg, 10%);

[0319](S)-3-Methyl-4-(3-phenylsulfonyl-quinolin-8-yl)-piperazine-1-carboxy-
lic acid tert-butyl ester was prepared in accordance with the procedure
described in Description 7 (D7) by replacing piperazine-1-carboxylic acid
tert-butyl ester with (S)-3-methyl-piperazine-1-carboxylic acid
tert-butyl ester. This material was then treated to the conditions
described in Example 2 (Alternative Procedure) to afford the title
compound (E15);

[0323]The dark solution was allowed to cool to room temperature,
dichloromethane (12.5 ml) was added and the solution was washed with
H2O (12.5 ml). The aqueous wash was extracted with dichloromethane
and the combined organic layers were extracted with 5M HCl (2×12.5
ml). The combined aqueous layers were washed with (dichloromethane 2.5
ml) then transferred to a conical flask, dichloromethane (12.5 ml) was
added and the flask was cooled in an ice/water bath. 10M Aqueous sodium
hydroxide (13 ml) was added whilst stirring, the mixture was then stirred
at room temperature until all the solids were dissolved. The lower
organic layer was removed and the aqueous layer was extracted with
dichloromethane (7.5 ml), the combined organic layers were concentrated
under reduce pressure to ˜5 ml. Isooctane (2.5 ml) was added to the
dark brown solution resulting in crystallisation, the mixture was stirred
at room temp for 5 min then isooctane (22.5 ml) was added over 5 min. The
mixture was aged at room temp for 11/2 hrs before being cooled in an
ice/water bath for 30 min, the mixture was filtered and the cake washed
with isooctane (5 ml). The cake was dried under reduced pressure to give
the title compound E16; yield 1.67 g, 75%.

[0325]A suspension of 3-phenylsulfonyl-8-piperazin-1-yl-quinoline (E16)
(200 mg, 0.55 mmol) in ethanol (4 ml) was treated successively with
acetic acid (100 μl), acetylaldehyde (100 mg, 2.3 mmol) and resin
bound Amberlyst cyanoborohydride (˜3 mmol/g, 0.5 g). The mixture
was stirred at ambient temperature for 18 hours then filtered and the
filtrate absorbed onto an SCX cartridge. This was washed with ethanol
then eluted with a solution of 3% ammonia in 7% aqueous methanol. The
solution was evaporated and the residue subjected to purification by
flash chromatography on silica gel (eluting with
dichloromethane-methanol-aq. NH3) to give a solution of the free
base of the title compound. this was evaporated and treated with 1M HCl
in ether then crystallised from isopropanol to give the title compound
(E17) as a yellow solid.

[0328]Examples 18-21 were prepared using the method described for Example
16 from the appropriate substituted 3-arylsulfonyl-8-iodoquinoline
(derived from the appropriate thiol, tabulated below, using General
Procedures 1 or 2) in place of 3-phenylsulfonyl-8-iodoquinoline (D6).

[0329]Examples 22-28 were prepared using the method described for Example
1 (Alternative Procedure 3) from the appropriate substituted
3-arylsulfonyl-8-iodoquinoline (derived from the appropriate thiol,
tabulated below, using General Procedures 1 or 2) in place of
3-phenylsulfonyl-8-iodoquinoline (D6).

[0330]Examples 29-34 were prepared using the method described for Example
13, using the appropriate substituted 3-arylsulfonyl-8-iodoquinoline
(derived from the appropriate thiol, tabulated below, using General
Procedures 1 or 2) in place of 3-phenylsulfonyl-8-iodoquinoline (D6).

[0336]3-Phenylsulfonyl-8-piperazin-1-yl-quinoline (E16) (0.1 g) was
dissolved in ethyl acetate (1.7 ml) with warming. On cooling the product
crystallised as needles. Solvent was allowed to evaporate to afford the
title compound in quantitative recovery. Melting point 158° C.

[0341]3-Phenylsulfonyl-8-piperazin-1-yl-quinoline (E16) (0.5 g) was
dissolved in isopropanol (5 ml) with warming. The solution was allowed to
cool to ambient then stirred overnight before cooling in an ice-water
bath for 15 min. The product was collected by filtration, and dried in
vacuo at 50° C. to give the title compound, 371 mg, 74%. Melting
point 164° C.

[0347]Compounds can be tested following the procedures outlined in
WO98/27081. The compounds of Examples E1-E14, E16-34 and E37-43 were
tested and showed good affinity for the 5-HT6 receptor, having pKi
values>8.0 at human cloned 5-HT6 receptors. The compounds of
examples E15 and E35-36 were also tested and showed good affinity for the
5-HT6 receptor, having pKi values 7.5 at human cloned 5-HT6
receptors.